Protein therapy, which delivers a therapeutic level of protein that may be absent or insufficient in an individual, is considered the ultimate hope for many incurable diseases. However, the application of peptide drugs and therapeutic proteins is limited by their poor stability and permeability in a physiological environment. Thus, there is a growing effort to circumvent these problems by designing nanostructures that can act as carriers for the delivery of therapeutic proteins.
For the systemic delivery of therapeutic proteins, nanoparticles have long been desired as ideal carriers due to the ease of controlling their structures and properties. Additionally, nanoparticles may be used for the targeted delivery of therapeutic agents to specific pathological sites, allowing for an increase-of-dose effect at the needed sites as well as decreasing any side effects. However, very few nanoformulations have currently been approved for use clinically or in clinical trials. One major obstacle for the in vivo use of nanoparticles is the rapid clearance of nanoparticles by the immune system, which leads to undesired pharmacokinetics and biodistribution. This problem renders most targeting strategies ineffective and reduces the efficacy of both approved nanoformulations and those still in development.
Currently, the main strategy for extending the circulation time of nanoparticles is to coat the particles with polyethylene glycol (PEGylation) to create “stealth” brushes that mimic cell glycocalyx. Indeed, PEGylation has been found to extend the circulation time of particles in vivo. However, up to 25% of patients have been found to exhibit anti-PEG antibodies prior to treatment or develop anti-PEG antibodies after the first administration of PEGylated nanoparticles. Thus, PEGylation of nanoparticles has little prospect of becoming a practical vehicle in the development of nanoparticle-based therapeutics.